Tchkonia, T

AbstractAimMuscle wasting is one of the factors most strongly predicting mortality and morbidity in critically ill intensive care unit (ICU). This muscle wasting affects both limb and respiratory muscles, but the understanding of underlying mechanisms and muscle‐specific differences remains incomplete. This study aimed at investigating the temporal expression and phosphorylation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway in muscle wasting associated with the ICU condition to characterize the JAK/STAT proteins and the related changes leading or responding to their activation during exposure to the ICU condition.MethodsA novel experimental ICU model allowing long‐term exposure to the ICU condition, immobilization and mechanical ventilation, was used in this study. Rats were pharmacologically paralysed by post‐synaptic neuromuscular blockade and mechanically ventilated for durations varying between 6 hours and 14 days to study muscle‐specific differences in the temporal activation of the JAK/STAT pathway in plantaris, intercostal and diaphragm muscles.ResultsThe JAK2/STAT3 pathway was significantly activated irrespective of muscle, but muscle‐specific differences were observed in the temporal activation pattern between plantaris, intercostal and diaphragm muscles.ConclusionThe JAK2/STAT3 pathway was differentially activated in plantaris, intercostal and diaphragm muscles in response to the ICU condition. Thus, JAK2/STAT3 inhibitors may provide an attractive pharmacological intervention strategy in immobilized ICU patients, but further experimental studies are required in the study of muscle‐specific effects on muscle mass and function in response to both short‐ and long‐term exposure to the ICU condition prior to the translation into clinical research and practice.

Senolytic drugs are agents that selectively induce apoptosis of senescent cells. These cells accumulate in many tissues with aging and at sites of pathology in multiple chronic diseases. In studies in animals, targeting senescent cells using genetic or pharmacological approaches delays, prevents, or alleviates multiple age‐related phenotypes, chronic diseases, geriatric syndromes, and loss of physiological resilience. Among the chronic conditions successfully treated by depleting senescent cells in preclinical studies are frailty, cardiac dysfunction, vascular hyporeactivity and calcification, diabetes mellitus, liver steatosis, osteoporosis, vertebral disk degeneration, pulmonary fibrosis, and radiation‐induced damage. Senolytic agents are being tested in proof‐of‐concept clinical trials. To do so, new clinical trial paradigms for testing senolytics and other agents that target fundamental aging mechanisms are being developed, because use of long‐term endpoints such as lifespan or healthspan is not feasible. These strategies include testing effects on multimorbidity, accelerated aging‐like conditions, diseases with localized accumulation of senescent cells, potentially fatal diseases associated with senescent cell accumulation, age‐related loss of physiological resilience, and frailty. If senolytics or other interventions that target fundamental aging processes prove to be effective and safe in clinical trials, they could transform geriatric medicine by enabling prevention or treatment of multiple diseases and functional deficits in parallel, instead of one at a time.

Cholangiocyte senescence has been linked to primary sclerosing cholangitis (PSC). Persistent secretion of growth factors by senescent cholangiocytes leads to the activation of stromal fibroblasts (ASFs), which are drivers of fibrosis. The activated phenotype of ASFs is characterized by an increased sensitivity to apoptotic stimuli. Here, we examined the mechanisms of apoptotic priming in ASFs and explored a combined targeting strategy to deplete senescent cholangiocytes and ASFs from fibrotic tissue to ameliorate liver fibrosis. Using a coculture system, we determined that senescent cholangiocytes promoted quiescent mesenchymal cell activation in a platelet‐derived growth factor (PDGF)‐dependent manner. We also identified B‐cell lymphoma‐extra large (Bcl‐xL) as a key survival factor in PDGF‐activated human and mouse fibroblasts. Bcl‐xL was also up‐regulated in senescent cholangiocytes. In vitro , inhibition of Bcl‐xL by the small molecule Bcl‐2 homology domain 3 mimetic, A‐1331852, or Bcl‐xL‐specific small interfering RNA induced apoptosis in PDGF‐activated fibroblasts, but not in quiescent fibroblasts. Likewise, inhibition of Bcl‐xL reduced the survival and increased apoptosis of senescent cholangiocytes, compared to nonsenescent cells. Treatment of multidrug resistance 2 gene knockout ( Mdr2−/− ) mice with A‐1331852 resulted in an 80% decrease in senescent cholangiocytes, a reduction of fibrosis‐inducing growth factors and cytokines, decrease of α‐smooth muscle actin–positive ASFs, and finally in a significant reduction of liver fibrosis. Conclusion: Bcl‐xL is a key survival factor in ASFs as well as in senescent cholangiocytes. Treatment with the Bcl‐xL‐specific inhibitor, A‐1331852, reduces liver fibrosis, possibly by a dual effect on activated fibroblasts and senescent cholangiocytes. This mechanism represents an attractive therapeutic strategy in biliary fibrosis. (H epatology 2018;67:247‐259).

Histone deacetylase 3 prevents chondrocytes from producing inflammatory mediators that prevent bone development.

ABSTRACT Cellular senescence is a fundamental mechanism by which cells remain metabolically active yet cease dividing and undergo distinct phenotypic alterations, including upregulation of p16Ink4a, profound secretome changes, telomere shortening, and decondensation of pericentromeric satellite DNA. Because senescent cells accumulate in multiple tissues with aging, these cells and the dysfunctional factors they secrete, termed the senescence-associated secretory phenotype (SASP), are increasingly recognized as promising therapeutic targets to prevent age-related degenerative pathologies, including osteoporosis. However, the cell type(s) within the bone microenvironment that undergoes senescence with aging in vivo has remained poorly understood, largely because previous studies have focused on senescence in cultured cells. Thus in young (age 6 months) and old (age 24 months) mice, we measured senescence and SASP markers in vivo in highly enriched cell populations, all rapidly isolated from bone/marrow without in vitro culture. In both females and males, p16Ink4a expression by real-time quantitative polymerase chain reaction (rt-qPCR) was significantly higher with aging in B cells, T cells, myeloid cells, osteoblast progenitors, osteoblasts, and osteocytes. Further, in vivo quantification of senescence-associated distension of satellites (SADS), ie, large-scale unraveling of pericentromeric satellite DNA, revealed significantly more senescent osteocytes in old compared with young bone cortices (11% versus 2%, p < 0.001). In addition, primary osteocytes from old mice had sixfold more (p < 0.001) telomere dysfunction-induced foci (TIFs) than osteocytes from young mice. Corresponding with the age-associated accumulation of senescent osteocytes was significantly higher expression of multiple SASP markers in osteocytes from old versus young mice, several of which also showed dramatic age-associated upregulation in myeloid cells. These data show that with aging, a subset of cells of various lineages within the bone microenvironment become senescent, although senescent myeloid cells and senescent osteocytes predominantly develop the SASP. Given the critical roles of osteocytes in orchestrating bone remodeling, our findings suggest that senescent osteocytes and their SASP may contribute to age-related bone loss. © 2016 American Society for Bone and Mineral Research

Considerable evidence implicates cellular senescence in the biology of aging and chronic disease. Diet and exercise are determinants of healthy aging; however, the extent to which they affect the behavior and accretion of senescent cells within distinct tissues is not clear. Here we tested the hypothesis that exercise prevents premature senescent cell accumulation and systemic metabolic dysfunction induced by a fast-food diet (FFD). Using transgenic mice that express EGFP in response to activation of the senescence-associated p16INK4a promoter, we demonstrate that FFD consumption causes deleterious changes in body weight and composition as well as in measures of physical, cardiac, and metabolic health. The harmful effects of the FFD were associated with dramatic increases in several markers of senescence, including p16, EGFP, senescence-associated β-galactosidase, and the senescence-associated secretory phenotype (SASP) specifically in visceral adipose tissue. We show that exercise prevents the accumulation of senescent cells and the expression of the SASP while nullifying the damaging effects of the FFD on parameters of health. We also demonstrate that exercise initiated after long-term FFD feeding reduces senescent phenotype markers in visceral adipose tissue while attenuating physical impairments, suggesting that exercise may provide restorative benefit by mitigating accrued senescent burden. These findings highlight a novel mechanism by which exercise mediates its beneficial effects and reinforces the effect of modifiable lifestyle choices on health span.